Compositions and methods of treating calcium renal stones

ABSTRACT

Methods and compositions useful for the treatment and prophylaxis of calcium renal stones in persons with hypocitraturia or undergoing allopurinol therapy are disclosed. The methods involve administering potassium citrate compositions to persons afflicted with or susceptible to calcium renal stone formations. A typical dosage scheme involves administering about 30 to 120 meq potassium citrate per day in divided doses. Such treatments are effective in dissolving existing calcium stones and preventing formation of new calcium stones. Moreover, the results of a comparative clinical assay indicate the potassium citrate is superior to sodium citrate in the treatment of uric acid lithiasis. Potassium citrate therapy averts calcium renal stone formation, a complication which is often associated with sodium citrate or sodium bicarbonate alkalinization therapy.

This application is a continuation of copending U.S. Pat. applicationSer. No. 019,056, filed Feb. 26, 1987, now U.S. Pat. No. 4,888,182 whichis a continuation-in-part of U.S. Pat. application Ser. No. 741,715,filed June 6, 1985, now abandoned which was a continuation of U.S. Pat.application 483,678, filed Apr. 11, 1983, now abandoned, all of whichare incorporated by reference herein.

BACKGROUND OF THE INVENTION

The present invention relates to methods and compositions for medicaltreatment; and more particularly, this invention relates to methods andcompositions for the treatment and prophylaxis of calcium renal stones.

Formation of stones within the urinary tract (clinically termednephrolithiasis) represents a common health disorder. In the UnitedStates an estimated 5-10% of the population will develop urinary stonesin their lifetime. Of these stones virtually all originate in thekidneys, while bladder stones are rarely encountered except inassociation with a foreign body. Nephrolithiasis, while usually notfatal, causes considerable suffering, morbidity and loss of work. Oftenit is a disease which recurs throughout a patient's lifetime.

The medical profession has become increasingly aware that recurrentformation of renal stones may be prevented by a variety of medicalinterventions in a significant number of patients at risk fornephrolithiasis. However, many treatment programs are usedindiscriminately without regard for the particular cause for stoneformation. For example, stones of renal origin may be broadlycategorized on the basis of their chemical composition as thosecontaining calcium, and those which do not. Calcareous renal stonesaccount for 80-90% of stones, and are principally composed of calciumoxalate (dihydrate or monohydrate) and calcium phosphate (apatite orrarely brushite and whitlockite). Further, calcareous renal stones canbe subdivided into physiological pathogenesis, for examplehypercalciuria, hyperuricosuria, hyperoxaluria and hypocitraturia.Non-calcareous renal stones include those containing uric acid, cystine,or magnesium ammonium phosphate (struvite).

Notwithstanding the various etiologies attributed to renal stoneformation, treatments have generally been randomly selected. Thus,orthophosphate and thiazide have been used in various forms ofhypercalciuric as well as in normo-calciuric states, and allopurinol hasbeen used in hyperuricosuria as well as in normouricosuria. With respectto non-calcareous renal stones, specifically uric acid lithiasis, animproved treatment program has virtually eradicated the incidence ofthis disease state. Unfortunately treatments effective for uric acidstones, specifically administration of sodium citrate and sodiumbicarbonate, appear to potentiate formation of calcium stones, (see e.g.Sakhaee, Nicar, Hill, and Pak, "Contrasting Effects of Potassium Citrateand Sodium Citrate Therapies on Urinary Chemistries and Crystallizationof Stone-Forming Salts", Kidney International, (V 24, pp. 348-351(1983)), incorporated by reference herein).

Coincident with the recognition of the above, the present applicantadvocates a more selective approach, in which specific treatments arechosen for particular causes of stone formation. This approachrecognizes the heterogeneity of pathogenic background fornephrolithiasis and tailors treatment programs to ameliorate, correct orprevent the specific underlying derangement.

The teachings of Kopp et al. (U.S. Pat. No. 4,289,750) and Helbig et al.(U.S. Pat. No. 4,405,596) are related to the processes of the presentinvention and are incorporated by reference herein. These U.S. patentsinvolve the administration of an alkali-acting substance, prototypicallysodium bicarbonate, to increase plasma bicarbonate level and inducealkalotic volume contraction. Kopp et al. (U.S. Pat. No. 4,289,750)state that although alkaline-acting substances other than sodiumbicarbonate may be used, the alkaline-acting substance "would be adaptedto release sodium and bicarbonate ions." (col 5, lines 40-44). Kopp etal. (U.S. patent number 4,289,750) further indicate that an appropriatedose regimen of alkali-acting substance would raise blood bicarbonatelevels by a 4 to 5 mEq/1 base excess value. As shown in Pak et al. (J.of Urol. vol. 134, pp 11-19, see Table 5 (1985)), incorporated byreference herein, an effective dose regimen of potassium citrate did notraise serum bicarbonate or CO₂ levels to more than a fraction of thisextent. It is also mentioned in Kopp et al. (U.S. Pat. No. 4,289,750)that its oral preparations "--are highly effective in increasing urinevolume when administered at correct minimum dosage levels--" (col. 7,lines 63-65). As shown later herein, particularly in Table I,administration of effective levels of potassium citrate induces but aminor and statistically non-significant increase in urine volume.

Both Kopp et al. (U.S. Pat. No. 4,289,750) and Helbig et al. (U.S. Pat.No. 4,405,596) focus primarily upon patients with altered function orrenal insufficiency. These clinical syndromes, particularly renalinsufficiency, are contraindicative of potassium citrate therapyaccording to the processes of the present invention because thepotassium citrate-based therapy might lead to hyperkalemia.

The alkaline-acting substances of Kopp et al. and Helbig et al. may becombined with additional active agents. Kopp et al. (U.S. Pat. No.4,289,750) state that potassemia (sic) may be corrected by including apotassium compound such as potassium chloride, potassium bicarbonate orpotassium citrate in the oral preparations of that invention. Thisreference further states that prevention of kidney stone formation orelimination of kidney stones may be encouraged by "inclusion in oralpreparations of substances such as alkali or alkali earth metalcitrates, or inclusion of urea itself". Thus one condition (potassemia)may be corrected, it is taught, by addition of a salt such as potassiumcitrate. Another condition (kidney stone presence or formation), it istaught, may be alleviated by the creation of a state of alkalotic volumecontraction with increased urine volume and then adding substances suchan alkali or alkali earth metal citrate. There is no indication in Koppet al. (U.S. Pat. No. 4,289,750) that, as described elsewhere herein,sodium citrate encourages calcareous kidney stone formation. Nor isthere any indication in Kopp et al., that specifically potassiumcitrate, on the contrary, alleviates this condition, even in the absenceof alkalotic volume contraction.

Helbig et al. (U.S. Pat. No. 4,405,596) state that, in theirpreparations containing alkaline-acting agents, cations other thansodium may be suitable but that sodium is preferred. It is indicated inHelbig et al. (U.S. Pat. No. 4,405,596), a continuation-in-part of Koppet al. (U.S. Pat. No. 4,289,750), that alkali or alkali earth metalsalts of citric acid may be used for prophylaxis and therapy of kidneystones. These salts are directed to be administered as `additionalactive agents` in conjunction with an alkaline-acting substance (col 1,lines 35-48). Additionally, Helbig et al. (U.S. Pat. No. 4,405,596)state that "the novel and essential characteristic of the oral dosageform of the invention is that resorbable bicarbonate ions are formed orreleased only in the intestine of a subject" (col. 5 lines 36-39). Thischaracteristic distinguished their `alkaline-acting` agent from othersubstances such as metallic citrates which do not intestinally releaseresorbable bicarbonate. Specific metallic citrates mentioned includedhexapotassium-hexasodium-heptacitrate-hydrate- and hexacalcium-hexasodium-heptacitrate-hydrate-complexes. As it may be seen from thesedescriptions, Kopp et al. (U.S. Pat. No. 4,289,750) and Helbig et al.(U.S. Pat. No. 4,405,596) provide no guidance to the discoveriesinherent in the present invention involving the use of potassium citratefree of substantial sodium and bicarbonate-releasing capability inintestinal lumen to effect a new cure for calcareous kidney stones.

The results of the present invention described herein clearlydemonstrate that the administration of potassium citrate (but not sodiumcitrate), unaccompanied by alkali-acting substances releasing intestinalbicarbonate, is an effective treatment for calcareous kidney stones.Thus, sodium citrate is ineffective for treatment of kidney stones andsodium bicarbonate or any other sodium salt in combination withpotassium citrate would detract from the therapeutic effectiveness ofthe potassium citrate by converting the potassium citrate to sodiumcitrate by equilibrium and ionic interchange.

In an earlier study, Rudman et al.(N. Eng. J. Med. Vol. 303, pp 657-661(1980)) described the oral administration of a "citrate punch"comprising sodium citrate and citric acid to patients withhypocitraturia. This reference showed no increase in urinary citratewhen patients were treated only with the "citrate punch". It was foundthat the hypocitraturia was corrected only when the "citrate punch"administration was accompanied by an intramuscular injection ofmagnesium sulfate. Although Rudman et al. acknowledged thathypocitraturia may result from hypokalemia or acidosis, no suggestion ofusing potassium citrate for treatment of calcareous kidney stones wasmade.

SUMMARY OF THE INVENTION

The present invention provides a method and compositions useful for thetreatment and prophylaxis of calcium renal stones in persons susceptibleto such stone formations. The method involves administering compositionsof potassium citrate to a patient afflicted with or susceptible tocalcium renal stone formation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of alkali therapy on new stone formation andpre-existing stones in patients with uric acid nephrolithiasis.

FIG. 2 shows the effect of potassium citrate treatment on urinary pH andundissociated uric acid. Significant difference from pre-treatment valueproduced by treatment is shown by * for p 0.05.

FIG. 3 shows the effect of potassium citrate treatment on new stoneformation. Each circle represents new stone formation. Each lineindicated study in a separate patient. Asterisk denotes patients withpreexisting stone when the treatment with potassium citrate was begun.The bottom seven patients took potassium citrate concurrently withallopurinol (A) or thiazide (T).

FIG. 4 shows the effect of potassium citrate therapy on urinary citrateand relative saturation ratio of calcium oxalate. Bars indicate mean±SEM. *=p 0.05.

FIG. 5 shows the effect of potassium citrate on new stone formation.Each line represents study in a separate patient. Asterisk before theline indicates presence of pre-existing renal stone(s). Each point showsnew stone formation. A=allopurinol, T=thiazide.

FIG. 6 shows the effect of thiazide treatment and thiazide and potassiumcitrate treatment on new stone formation. Each line represents the studyin a separate patient. Each point indicates new stone formation.Combined thiazide and potassium citrate treatment was begun immediatelyafter thiazide treatment.

FIG. 7 shows the effect of potassium citrate therapy on new stoneformation. Each line represents one patient. An asterisk before the lineindicates presence of preexisting stone(s). Each point shows new stoneformation. A=allopurinol; T=thiazide.

FIG. 8 shows the effect of long term treatment with potassium citrate onstone formation. Each line represents separate patient; each circle, newstone episode. Asterisk before line indicates preexisting stones beforeinstitution of treatment. For first three patients, thiazide treatmentis shown by T.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention will be described in terms of preferred embodiments whichrepresent the best mode known to the applicant at the time of thisapplication.

In-depth metabolic studies on the part of applicant has revealed thesurprisingly unexpected and unobvious superiority of potassium citratetherapy over sodium alkali therapy in the management of nephrolithiasis.(Sakhaee et al., Kidney International, V 24, pp 348-352, (1983)).Specifically, in patients with both uric acid and calciumnephrolithiasis, potassium citrate therapy causes a greater decline inurinary calcium and a greater rise in urinary citrate. Urinary sodiumincreases with sodium citrate therapy but not with potassium citrate. Nosignificant or consistent changes occur in urinary uric acid, phosphateor oxalate. With both treatments, urinary pH rises to about anequivalent degree.

As reflected by the above described changes, potassium citrate iseffective in lowering urinary saturation of calcium oxalate, does notcause a rise in sodium urate saturation, and produces a rise in urinaryinhibitor activity against calcium oxalate nucleation. In contrast,sodium citrate raises the saturation of sodium urate and increasesformation calcium oxalate stones.

Moreover, in patients with uric acid lithiasis, treatment with sodiumalkali is associated with calcium stone formation (Pak, et al., KidneyInternational, V 30, pp 422-428, (1986)). The substitution of potassiumcitrate for sodium citrate inhibits calcium stone formation.

Consistent with the clinical findings of applicant's research, potassiumcitrate therapy is useful in the prevention of uric acid or cystinelithiasis since it is a good alkalizing agent. More importantly,potassium citrate therapy averts the complication of calcium stoneformations in patients afflicted with uric acid or cystine lithiasis (ascontrasted with treatment with sodium alkali which may potentiatecalcium stone formation). Further, potassium citrate therapy iseffective in restoring normal citrate in patients with hypocitraturialinked calcium nephrolithiasis and coincidently inhibits and dissolvescalcium stone formations. The ability to dissolve calcium stones isheretofore an unreported finding with any medical treatment;conventional alkali therapy has customarily been associated withformation of calcium stones as stated in textbooks, pointing touniqueness of this invention. Coincidentally, thiazide treatment hasbeen shown to cause hypocitraturia and recurrent calcium stoneformation. Adding potassium citrate could prevent hypocitraturia andavert calcium stone formation, emphasizing another very novel finding ofthis invention.

Typically, a dosage range of 30-120 meq potassium citrate per day givenin divided doses is effective in preventing and treating calcium renalstones in patients afflicted with or susceptible to calcium stoneformation. Generally recognized solid or liquid pharmaceutical form suchas tablets, capsules, effervescent tablets, chewable tablets, solutionsor syrups, are acceptable in delivering potassium citrate.

Examples of medicinal formulations in accordance with the presentinvention include:

    ______________________________________                                        Potassium Citrate Drink Mix                                                                        Percent (w/w)                                            Potassium Citrate, U.S.P.                                                                          21.63                                                    Fructose, U.S.P.     70.00                                                    Flavor               2.37                                                     Citric Acid, U.S.P.  5.00                                                     Calcium Phosphate, Tribasic, N.F.                                                                  1.00                                                     to be dissolved in water (sufficient to produce 2 meq/ml)                     prior to patient administration.                                              Potassium Citrate Tablet (5 meq)                                                                   mg/Tablet                                                Potassium Citrate, U.S.P.                                                                          540.5                                                    Carnauba Wax, N.F.   200.0                                                    Talc, U.S.P.         40.0                                                     Magnesium Stearate, N. F.                                                                          5.0                                                      ______________________________________                                    

In addition, K-Lyte (Mead Johnson Pharmaceutical Division, Evansville,Ind.) a mixture of potassium bicarbonate and potassium citrate is usefulin the methods prescribed by this invention. Another useful preparationmay be a mixture of potassium bicarbonate or potassium carbonate andcitric acid.

In order that the invention may be more clearly understood, preferredembodiments will be further described in terms of the following examples(updated since the original patent application), which should not beconstrued to limit the scope of this invention.

The data describing these examples have largely been published inpeer-reviewed reputable medical journals since the original patentapplication, indicating novelty and importance of this invention.Potassium citrate has also been approved as a prescription drug by theFDA (Food and Drug Administration) for the treatment of calcium renalstones as described herein, further supporting uniqueness of theinvention. (NDA No. 19,071 was granted to the inventor in July, 1985).

EXAMPLE 1 Comparative Analysis of Potassium Citrate and Sodium CitrateTherapies

An important determinant for the formation of uric acid stones is thepassage of uncommonly acid urine. The urinary pH in patients with uricacid lithiasis is typically less than the dissociation constant (pKa) ofuric acid of 5.47; thus, their urinary environment is supersaturatedwith respect to uric acid. Because uric acid is unstable and moresoluble at a higher pH, it has been customary to recommendalkalinization of urine for management of uric acid nephrolithiasis.Principally owing to their ready commercial availability, sodium ratherthan potassium salts of bicarbonate and citrate have been used asalkalinizing agents.

Although it may cause dissolution or inhibit formation of uric acidstones, sodium alkali therapy is often complicated by the development ofcalcium-containing renal stones (calcium phosphate and/or calciumoxalate). This study indicates that potassium alkali therapy may avertsuch a complication in uric acid lithiasis. Moreover, the treatment withpotassium citrate has shown to correct hypocitraturia (low urinarycitrate), a defect frequently encountered in calcium nephrolithiasis.Thus, these findings suggest that potassium alkali is also useful in themanagement of calcium urolithiasis associated with hypocitraturia.

Five patients with documented uric acid lithiasis, who developed calciumstone complication on sodium alkali treatment, participated in thisstudy (Sakhaee, Nicar, Hill and Pak, Kidney International, V 24, pp348-352, (1983)). All subjects had adequate endogenous creatinineclearance, ranging from 75-130 ml/min. None of the participatingsubjects suffered from hyperkalemia, fluid retention, urinary tractinfection, or urinary tract obstruction during the study. Among patientswith uric acid lithiasis, one suffered from gout. None had chronicdiarrheal syndrome.

The study comprised three phases, consisting of control phase (no drug),potassium citrate phase, and sodium citrate phase, conducted in randomorder. The dosage of the two forms of alkali were the same (60 mg./dayin three divided doses orally). All other drugs were withheld during thestudy. Each phase was four weeks in duration. After three weeks ofstabilization in an outpatient setting, patients underwent an inpatientevaluation during the last week.

During each inpatient evaluation, subjects were maintained on a constantmetabolic diet with a daily composition of 400 mg calcium, 800 mgphosphorous, 100 meq sodium, 60 meq potassium and sufficient fluid toensure approximately two liters of urine daily for the entire studyperiod of six days. After three days of stabilization, urine wascollected daily in 24-hour pools during last three days for totalvolume, pH, calcium, oxalate, phosphorous, sodium, potassium, magnesium,ammonium, citrate, sulfate, and uric acid; relative saturation ration(RSR) of monosodium urate and monopotassium urate; activity productration (APR) of brushite (CaHPO₄.2H₂ O) and calcium oxalate; andformation product ration (FPR) of brushite and calcium oxalate.

                  TABLE I                                                         ______________________________________                                        Effect of Alkali Therapies on Urinary Chemistries and                         Crystallization in Patients with Uric Acid Lithiasis                                             Potassium  Sodium                                                    Control  Citrate    Citrate                                         ______________________________________                                        Total Volume                                                                              2456 ± 290                                                                            2525 ± 359                                                                            2669 ± 296                               ml/day                                                                        pH          5.35 ± 0.18                                                                           6.68 ± 0.14                                                                           6.73 ± 0.20                              Calcium, mg/day                                                                           154 ± 47                                                                              99 ± 23 139 ± 24                                 Citrate, mg/day                                                                           398 ± 119                                                                             856 ± 103                                                                             799 ± 89                                 Uric Acid, mg/day                                                                         417 ± 121                                                                             522 ± 171                                                                             512 ± 132                                Activity Product Ratio (APR)                                                  Calcium Oxalate                                                                           3.21 ± 0.96                                                                           1.69 ± 0.76                                                                           2.21 ± 0.63                              Brushite    0.04 + 0.03                                                                              0.74 ± 0.22                                                                           1.17 ± 0.44                              Formation Product Ratio (FPR)                                                 Calcium Oxalate                                                                           16.1 ± 5.6                                                                            22.2 ± 6.6                                                                            14.1 ± 5.3                               Relative Saturation Ratio (RSR)                                               Monosodium Urate                                                                          0.51 ± 0.20                                                                           0.95 ± 0.33                                                                           1.45 ± 0.44                              Monopotassium                                                                             0.05 ± 0.02                                                                           0.33 ± 0.07                                                                           0.12 ± 0.04                              Urate                                                                         ______________________________________                                    

A review of the above results indicates that, in patients with uric acidlithiasis, both alkali therapies caused a significant decline in urinarysaturation (APR) of calcium oxalate; however, the decline was moreprominent during potassium citrate therapy than during sodium alkalitherapy. Thus, urinary saturation of calcium oxalate declined duringalkali therapies, more so when potassium citrate was given. Urinary APR(saturation) of brushite increased during both alkali therapies; therise was more prominent during sodium citrate therapy. Urinaryenvironment became supersaturated (APR 1) with respect to brushiteduring sodium alkali treatment, whereas it remained undersaturated whenpotassium citrate was given.

The urinary FPR (a measure of inhibitor activity) of calcium oxalaterose significantly during oral potassium citrate treatment. Thus,spontaneous precipitation of calcium oxalate commended at a higher leverof supersaturation when potassium citrate was given. However, FPR ofcalcium oxalate did not change significantly during sodium citratetherapy. The difference in FPR between the two alkali phases wassignificant. In 2 of 5 patients, FPR decreased by more than 30%; thus,spontaneous precipitation was facilitated in some patients.

The saturation of monosodium urate (RSR) rose significantly during bothalkali phases, more so during sodium citrate therapy. The urinaryenvironment became supersaturated with respect to monosodium urateduring sodium citrate therapy, but remained undersaturated whenpotassium citrate was given. The saturation of monopotassium urate (RSR)increased significantly during both alkali treatments, but more soduring potassium citrate therapy.

The results of this study disclose that both potassium citrate andsodium citrate are effective in the prevention of uric acid lithiasissince both alkali increased urinary pH (and therefore increased thesolubility of uric acid).

However, the results suggest that sodium citrate does not prevent thecomplication of calcium nephrolithiasis when given to patients with uricacid stones. It might cause this complication because of increasedurinary saturation of calcium phosphate, and in some patients when theeffect of monosodium urate-induced calcium oxalate crystallizationoverrides the inhibitory action of citrate.

In contrast to the action of sodium citrate, potassium citrate at anequimolar dosage significantly reduced urinary calcium excretion whileincreasing urinary citrate excretion. This study therefore indicatedthat potassium citrate, unlike sodium citrate, prevent the complicationof calcium oxalate nephrolithiasis when given to patients with uric acidlithiasis. This prevention involved reducing urinary saturation bycalcium oxalate and inhibiting spontaneous precipitation of calciumoxalate. The potassium citrate-containing compositions of the presentinvention preferably comprise less than about ten weight percent sodiumsalts and more preferably are substantially free of sodium salts.

EXAMPLE II Potassium Citrate is Effective in Preventing Calcium StoneFormation (in 5 Patients with Uric Acid Stones) Caused by Sodium AlkaliTherapy

Detailed case reports were obtained in 5 patients with uric acidnephrolithiasis showing different response between sodium alkali andpotassium alkali treatment (Pak et al., Kidney International, V 30, pp422-428, (1986)). Before treatment, they had surgically removed orspontaneously passed stones which were pure uric acid in composition.When sodium alkali was given (as bicarbonate or citrate, 60-118 meq/day,in one case as a mixture with potassium alkali), new stone formationcontinued in 4 patients, and a radiolucent (uric acid) stone became"calcified" in the remaining patient. The stone analysis disclosedcalcium oxalate in 5 patients and calcium phosphate in three patients.

When potassium citrate (in 4 cases) or potassium bicarbonate (in 1patient) was administered in place of the sodium alkali over 1 to 3.5years (at a dosage of 60-80 meq/day, no new stones were formed (onepassed by case 5 was a preexisting stone) (FIG. 1).

In summary, five patients with known uric acid stones had a complicationof calcium stones during sodium alkali therapy (alone or in combinationwith potassium alkali). Both calcium and uric acid stone formationceased when patients were treated with potassium citrate (orbicarbonate).

EXAMPLE III Long-Term Prevention of Stone Formation by Potassium CitrateTherapy in Patients with Uric Acid Nephrolithiasis with or withoutComplication of Calcium Renal Stone

Eighteen patients with uric acid nephrolithiasis (six with uric acidstones alone and 12 with both uric acid and calcium stones) underwentlong-term treatment (1-5.33 years) with potassium citrate (30-80meq/day) (Pak, et al, Kidney International, V 30, pp 422-428, (1986)),urinary pH increased from low (5.3±0.31) to normal (6.19 to 6.46) duringtreatment (FIG. 2). Consequently, the urinary content of undissociateduric acid, which was high to begin with, decreased to the normal rangeduring treatment, making uric acid precipitation unlikely (FIG. 2).Urinary citrate rose from 503±225 mg/day to 852-998 mg/day. Urinarysaturation of calcium oxalate declined with potassium citrate treatment.New stone formation (either uric acid or calcium stone) declined from1.20±1.68 stone/patient year to 0.01+0.04 stones/patient year (FIG. 3).94.4% of patients did not form further stones.

These results, showing that potassium citrate is effective in themanagement of uric acid lithiasis presently with or without calciumstones, are the basis for the FDA approval of potassium citrate as aprescription drug for this condition in July, 1985.

The above observation has since been confirmed by Dr. Nector Tomyez(endocrinologist) and Dr. Richard Lewis (urologist) who have written tothe inventor's group (letters available upon request).

EXAMPLE IV Potassium Citrate Therapy is Effective in Dissolving ExistingCalcium Containing Renal Stones

Prior to institution of potassium citrate therapy, 33 patients hadpreexisting radiopaque calculi (calcium stones) visualized on abdominalroentgenograms (Pak et al., Trans. Assoc. Amer. Physic, V 96, pp294-305, (1983)). Repeat examination after 8 months to 2 years ofpotassium citrate therapy showed a reduced number of stones in 14patients. In 4 of them, this reduction could be attributed to thepassage of stones. However, there were fewer stones visualized in 6patients even though they did not remember passing stones. In theremaining patients, the number of stones passed could not entirelyaccount for the reduced number of stones.

Thus, long-term potassium citrate treatment dissolved calcium stoneslocated in kidneys of patients with stones. There is no prior knowndocumented report of dependably dissolving calcium stones by any medicaltreatment.

EXAMPLE V A Case History Showing Dissolution of Calcium Stones byPotassium Citrate Therapy

A 62-year-old white woman with incomplete renal tubular acidosis passedapproximately 400 stones during the preceding three years, as often asone a day in recent months. Stones were composed of calcium phosphateand calcium oxalate. Urinary citrate was very low at 34 mg/day. Onpotassium citrate therapy (20 meq four times/day), urinary citrateincreased to 333-376 mg/day.

She passed only eight stones during twenty months of treatment.Abdominal X-ray taken at fourteen months of treatment disclosed markedchanges. Before treatment, she had numerous radioopaque calculi in bothkidneys. After treatment, stones in the mid and lower pole of rightkidney and mid-portion of left were no longer seen.

EXAMPLE VI Potassium Citrate Effectively Prevents New Stone Formation inPatients with Distal Renal Tubular Acidosis

Distal renal tubular acidosis is a common cause of hypocitraturia andintractible calcium nephrolithiasis. The effect of oral potassiumcitrate therapy in 9 patients with incomplete distal venal tubularacidosis was examined (Preminger et al., J. Urology, V 134, pp 20-23(1985)). Potassium citrate (60-60 meq/day in divided doses)significantly increased urinary citrate, and lowered urinary calciumThus, the urinary saturation of calcium oxalate significantly decreasedduring treatment while that of brushite (Ca phosphate) did not change.

During a mean treatment period of 34 months, none of nine patientsformed new stones, although the same patients had formed an average of39.3 stones/year during the three years prior to treatment.

Thus, potassium citrate therapy was effective in correcting biochemicalabnormalities and preventing recurrent calcium stone formation inpatients with distal renal tubular acidosis. The novelty of this findingwas supported by the acquisition, by the inventor, of a new drugapplication from the FDA for this condition in July, 1985.

Recent studies by the inventor's laboratory in 6 patients with distalrenal tubular acidosis indicated that sodium citrate was not asadvantageous a treatment agent as was potassium citrate. Urinary calciumremained high at 216 mg/day (from a control value of 214 mg/day) duringsodium citrate (60 meq/day) treatment, whereas it decreased to 178mg/day during potassium citrate (60 meq/day) treatment. Urinary citrateincreased to a lesser degree (493 mg/day from 253 mg/day) during sodiumcitrate therapy, then during potassium citrate treatment (575 mg/day).The urinary saturation of calcium phosphate rose by 37% during sodiumcitrate treatment, whereas it was unaltered by potassium citratetreatment. Thus, sodium alkali therapy may not be an effective in, ormay even exaggerate, calcium stone formation in renal tubular acidosis.

EXAMPLE VII Potassium Citrate Effectively Prevents New Stone Formationin Patients with Chronic Diarrheal Syndrome

Long-term effects of potassium citrate therapy (60-80 meq/day in 3-4divided doses) on urinary biochemistry and on stone formation wereexamined in 10 patients with calcium oxalate nephrolithiasis due tochronic diarrheal syndrome (regional enteritis, jejuno-ileal bypasssurgery, partial gastrectomy or ulcerative colitis). Urinary citrate waslow (320 mg/day) in 9 patients, and urinary oxalate was high in 4patients. Potassium citrate therapy caused a sustained increase inurinary citrate from 148±154 (SD) mg/day to 333-615 mg/day, and produceda sustained reduction in urinary saturation (RSR) of calcium oxalate(FIG. 4). During a mean treatment period of 3.2 years, stone formationrate declined from 4.69±10.12 to 0.71±1.44 stones/patient year (p 0.01),and 7 patients (70%) remained stone-free (FIG. 5). Thus, potassiumcitrate represents an important therapeutic modality in the managementof hypocitraturic calcium oxalate nephrolithiasis due to chronicdiarrheal syndrome.

The failure of Rudman et al., N. Engl. J. Med., V 303, pp 657-661(1980)) to show a significant rise in urinary citrate with sodiumcitrate-citric acid in patients with hypocitraturia of gastrointestinalorigin emphasizes the uniqueness of potassium citrate action.

EXAMPLE VIII Potassium Citrate Therapy Prevents Hypocitraturia Caused byThiazide Treatment of Hypercalciuric Calcium Nephrolithiasis

Thirteen patients with hypercalciuric calcium renal stones were treatedwith thiazide, a treatment widely used for this condition because of itsability to lower urinary calcium. Even though urinary calcium decreasedfrom 303±119 mg/day to 193± mg/day on treatment, they continued to formkidney stones (6.62 to 5.12 stones/patient year) (Pak et al., Amer.Jrnl. of Med., V 79, pp 284-288 (1985)).

Because they had hypocitraturia (250 mg/day), potassium citrate (30-60mg/day in divided doses) was added to the ongoing treatment program.During combined treatment with thiazide and potassium citrate, urinarypH significantly rose and normal urinary citrate was restored. Tenpatients stopped forming stones. Stone formation significantly declinedfrom 5.12 stones/patient year to 0.05 stones/patient year (FIG. 6).

This novel discovery, showing effectiveness of potassium citrate inpatients who continue to form stones on thiazide, was the basis for theNDA approval acquired by the inventor for potassium citrate to be usedconcurrently with thiazide in hypercalciuric nephrolithiasis. Thisfinding has been confirmed by cooperative studies of Dr. Donald Griffithat Houston (a part of NDA 19,071 report, available upon request).

In that study, Dr. Griffith studied 29 patients with hypercalciuriccalcium nephrolithiasis who continued to form stones on thiazidetherapy. Potassium citrate was added to the ongoing thiazide treatmentprogram. None of 29 patients formed any stone on combinedthiazide-potassium citrate treatment. New stone formation declined from0.64 stones/patient year to zero.

EXAMPLE IX Potassium Citrate is Effective in Preventing Stone Formationin Patients with Idiopathic Hypocitraturic Calcium OxalateNephrolithiasis

The effects of long-term treatment with potassium citrate (30-80meq/day) were examined in 37 patients with idiopathic-hypocitraturiccalcium oxalate nephrolithiasis, in whom the main causes ofhypocitraturia (renal tubular acidosis, chronic diarrhea or hypokalemia)were excluded or considered unlikely (Pak, et al., Annuls of Internal.Med., V 104, pp 33-37 (1986)).

Potassium citrate treatment produced a sustained increase in urinarycitrate excretion from an initially low value (223 to 253 mg/day) towithin normal limits (470 to 620 mg/day). Urinary pH rose significantlyand was maintained at 6.5 to 7.0. Along with these changes, urinarysaturation of calcium oxalate significantly declined to normal. Furtherstone formation ceased in 89.2% of patients during treatment, and newstone formation rate declined from 2.11 stones/patient year to 0.28stones/patient year (FIG. 7).

This indication for potassium citrate treatment was again approved bythe FDA in awarding an NDA to the inventor in July, 1985.

EXAMPLE X Prevention of Calcium Stone Formation by Potassium Citrate inPatients with Hyperuricosuric Calcium Oxalate Nephrolithiasis

Previous examples, all updated and validated by publications inpeer-reviewed journals, were contained or described, at least in apreliminary form, in the original patent application (U.S. Ser. No.483,678). However, this Example represents a new finding heretofore notspecifically mentioned (published in May, 1986).

Calcium renal stone formation in patients with high urinary uric acid(hyperuricosuric calcium oxalate nephrolithiasis) is believed to be dueto the induction of the crystallization of calcium oxalate by monosodiumurate. The present Example shows that citrate, when added to a syntheticsolution metastably supersaturated with respect to calcium oxalate,inhibited heterogeneous nucleation (induction of crystallization) ofcalcium oxalate by monosodium urate (Pak et al., Archive Internal. Med.,V 146, pp 863-867, (1986)).

Long-term treatment with potassium citrate (60-80 meq/day) wasundertaken to determine whether induced hypercitraturia could preventcalcium oxalate stone formation in 19 patients with hyperuricosuria. Thetreatment produced a sustained rise in urinary pH and citrate, and areduction in urinary saturation of calcium oxalate and in the urinarycontent of undissociated uric acid. Stone formation declined from1.55/patient year to 0.38/patient year and ceased in 16 of 19 patients(FIG. 8). This finding, showing effectiveness of potassium citrate inpreventing calcium stone formation in patients with hyperuricosuria,represents a heretofore unreported unique demonstration.

While the methods of this invention have been described in terms ofpreferred embodiments, it will be apparent to those of skill in the artthat various changes may be made in the methods disclosed withoutdeparting from the scope of the invention, which is defined by thefollowing claims.

What is claimed is:
 1. A method for prevention of calcium renal stoneformation in a person having hypocitraturia and being susceptible tosuch stone formation and for dissolution of calcium renal stones andprevention of further calcium renal stone formation in a person havinghypocitraturia and being afflicted with calcium renal stones, the methodcomprising: administering to a person having hypocitraturia a daily oraldosage of a composition comprising potassium citrate, the daily oraldosage containing potassium citrate in an amount between about 30 meqand about 120 meq.
 2. The method of claim 1 wherein the administeringstep alleviates the hypocitraturia.
 3. The method of claim 1 wherein thehypocitraturia is associated with thiazide therapy.
 4. The method ofclaim 1 wherein the hypocitraturia is associated with renal tubularacidosis.
 5. The method of claim 1 wherein the hypocitraturia isassociated with chronic diarrhea.
 6. The method of claim 1 wherein thehypocitraturia is idiopathic.
 7. A method for prevention of calciumrenal stone formation in a person undergoing allopurinol treatment andbeing susceptible to such stone formation and for dissolution of calciumrenal stones and prevention of further calcium renal stone formation ina person having hypocitraturia and being afflicted with calcium renalstones, the method comprising:administering to a person undergoingallopurinol treatment a daily oral dosage of a composition comprisingpotassium citrate, the daily oral dosage containing potassium citrate inan amount between about 30 meq and about 120 meq.
 8. The method of claim1, or 7 wherein the composition is a liquid pharmaceutical compositionor an effervescent tablet preparation.
 9. The method of claim 1, or 7wherein the daily oral dosage comprises two to four about equallydivided doses.
 10. The method of claim 1, or 7 wherein the compositionis in a tablet form.
 11. The method of claim 1, or 7 wherein thecomposition is a liquid pharmaceutical composition or an effervescenttablet preparation.
 12. The method of claim 1, or 7 wherein thecomposition comprises a pharmaceutically acceptable carrier which slowlyreleases potassium citrate.
 13. The method of claim 1, or 7 wherein thecomposition comprises carnauba wax.
 14. The method of claim 1, or 7wherein the composition comprises less than about ten weight percentsodium salts.
 15. The method of claim 1, or 7 wherein the composition issubstantially free of sodium salts.